A LINE-1 component to human aging: do LINE elements exact a longevity cost for evolutionary advantage?

Abstract

Advancing age remains the largest risk factor for devastating diseases, such as heart disease, stroke, and cancer. The mechanisms by which advancing age predisposes to disease are now beginning to unfold, due in part, to genetic and environmental manipulations of longevity in lower organisms. Converging lines of evidence suggest that DNA damage may be a final common pathway linking several proposed mechanisms of aging. The present review forwards a theory for an additional aging pathway that involves modes of inherent genetic instability. Long interspersed nuclear elements (LINEs) are endogenous non-LTR retrotransposons that compose about 20% of the human genome. The LINE-1 (L1) gene products, ORF1p and ORF2p, possess mRNA binding, endonuclease, and reverse transcriptase activity that enable retrotransposition. While principally active only during embryogenesis, L1 transcripts are detected in adult somatic cells under certain conditions. The present hypothesis proposes that L1s act as an 'endogenous clock', slowly eroding genomic integrity by competing with the organism's double-strand break repair mechanism. Thus, while L1s are an accepted mechanism of genetic variation fueling evolution, it is proposed that longevity is negatively impacted by somatic L1 activity. The theory predicts testable hypotheses about the relationship between L1 activity, DNA repair, healthy aging, and longevity.

Figure 1. Aging theories converge on accumulated DNA damage

Exogenous factors, such as UV irradiation, caloric excess, alterations in the IGF/mTOR pathways, and oxidative stress can alter the cellular balance between DNA damage and repair. Similarly, endogenous pathways such as telomere regulation and genetic defects in DNA repair can lead to cellular senescence and premature aging. These effects are of added importance when they alter stem cell regenerative activity.

Figure 2. The L1 life cycle facilitates genomic integration of RNA transcripts

1) L1 transcription and 3′ transduction. 2) L1 transcripts are exported to the cytoplasm. 3) L1 transcripts undergo bicistronic translation of ORF1 and ORF2 yielding ORF1p and ORF2p, respectively. 4) L1 ORF1p binds L1 transcripts in the cytoplasm and form a ribonucleoprotein complex. 5) The L1 RNP complex migrates to the nucleus. 6) ORF2p nicks the genomic DNA and initiates target-primed reverse transcription (TPRT). 7) Integration occurs in the genomic DNA, which increases genome size, promotes exon shuffling, and increases L1 & Alu copy number.

Figure 3. Cellular mechanisms limiting selfish retroelements in mammals

L1 transcription is suppressed by DNA methylation and can be interrupted by premature polyadenylation. An antisense promoter residing within the L1 promoter can generate antisense L1 transcripts and lead to transcription of neighboring 5′ sequences. RNA interference can also regulate L1 post-transcriptionally via small RNAs facilitated by Argonaute and PIWI proteins. Small RNAs may in-turn direct DNA methylation.

Figure 4. LINEage Theory

Acute stress can activate L1 elements leading to transient DNA damage, and rarely to insertional events, which accumulate over a lifetime. L1 ORF1p and ORF2p are equipped with capabilities to alter the genomic landscape that has accelerated evolution, but at the expense of accumulated DNA damage and altered cell fate. This dichotomous nature of L1 may represent another example of antagonistic pleiotropy.